The drug discovery process is currently undergoing a fundamental revolution as it embraces `functional genomics`, that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on `positional cloning`. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterize further genes and their related polypeptides/proteins, as targets for drug discovery.
Membrane-Type Matrix Metalloproteinases (MT-MMPs) are a new family of transmembrane matrix metalloproteinases. At present, there are four human MT-MMPs published in the literature (Sato, H. et al., Nature 370:61-65, 1994; Will, H. and Hinzmann, B. Eur. J. Biochem. 231:602-608, 1995; Takino, T. et al., J. Biol. Chem. 270:23013-23020; Puente, X. S. et al., Cancer Res. 56:944-949, 1996). Recently, a fifth MT-MMP (MT-MMP-5) has been published for mouse (Pei, D., J. Biol. Chem. 274:8925-8932, 1999). Also, a splice variant for human MT-MMP-5 in which the catalytic domain is missing has been patented (U.S. Pat. No. 5,937,508).
MT-MMPs function as both a receptor and as an activator for certain MMPs and serve to localize extracellular matrix proteolysis at the pericellular region. MT-MMPs have been shown to play a role in matastasis and have been identified in numerous carcinomas. An MT-MMP has also been demonstrated to be involved in Alzheimer's Disease where it has been found in white matter microglia (Yamada, T. et al., Acta Neuropathol, 90:421-424, 1995). MT-MMPs may also play a role in the infiltration of inflammatory cells. By Northern Array Grid Analysis, MT-MMP5-L expression was detected in cerebellum and kidney. A multiple tissue Northern blot was also probed for MT-MMP5-L where it was identified in brain, kidney and pancreas. This indicates that these Membrane-Type Matrix Metalloproteinase have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of Membrane-Type Matrix Metalloproteinase family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, 1) brain-related diseases including diabetes, polycystic kidney disease, renal failure, etc., 2) brain related diseases including Alzheimer's disease, stroke multiple sclerosis, neurodegenerative diseases, etc., 3) cardiovascular diseases including restenosis, myocardial infarction, dilated cardiomyopathy, atherosclerosis, etc., and 4) others such as inflammation and cancer.